Recently, along with the aging population in Japan, senile dementia has become a significant social problem. Currently, one out of every ten people over the age of sixty-five has dementia, and the number of senior citizens who are cognitively impaired is expected to rise from the current level of 1.3 million to 3.0 million by the year of 2035. Although the majority of those with dementia have multi-infarct dementia and Alzheimer's disease (AD), approximately one-half of the abovementioned people have Alzheimer's disease. The former has been effectively coped with using medical countermeasures, such as blood pressure control or relapse prophylaxis. However, the cause of Alzheimer's disease, a therapeutic method, and a preventive method therefor are still unclear, and thus immediate medical solutions are being sought. Moreover, with regard to types of dementia other than Alzheimer's disease, in addition to the abovementioned multi-infarct dementia, other forms of dementia specifically referred to as tauopathies also exist (e.g., frontotemporal dementia, dementia with Lewy Bodies, cortico-basal degeneration, and progressive supranuclear palsy), and since the symptoms of these are similar to those of Alzheimer's disease, clinically differentiating these diseases from Alzheimer's disease is difficult. However, if Alzheimer's disease can be differentially diagnosed by being differentiated from other types of dementia before the symptoms of dementia become an impediment, the establishment of an early diagnostic method for Alzheimer's disease is imperative, in order for recently tested therapeutic methods to be started even earlier, and for the progression of dementia to be slowed.
In Alzheimer's patients, atrophy of the cerebral cortex is seen, and pathologically, in addition to a high degree of neuronal loss, characteristic lesions such as neurofibrillary tangles or senile plagues are observed. Among these, senile plague is thought to be the earliest manifested and most significant change in Alzheimer's disease out of the characteristic changes thereof. The major component of senile plague is amyloid β-protein (Aβ), and since there are mutations in β-amyloid precursor protein (βAPP), which is an Aβ precursor gene in familial Alzheimer's disease showing autosomal dominant inheritance, the abnormal degradation or production of Aβ is thought to be strongly related to the pathogenesis and progress of Alzheimer's disease. Aβ is generated by being sequentially cleaved from β-amyloid precursor protein by β-secretase and γ-secretase (presenilin complex), a type of aspartic protease.
As a therapeutic agent for Alzheimer's disease, the insufficient acetylcholine compensatory effects of acetylcholinesterase inhibitors and the like are known. However, various signal transduction targeting agents that are based on the abovementioned mechanism are also being developed.
Diagnosis of Alzheimer's disease (senile dementia of Alzheimer's type) is clinically performed based on whether various diagnostic standards have been satisfied. In order to accomplish this, a detailed medical history is taken and various medical tests are performed, such as a functional neuroimaging test, a physiological test, a neuropsychological test, and an examination of clinical symptoms. However, in the early stages of Alzheimer's disease there are almost no specific abnormal findings upon examination, and therefore a high amount of reliance is currently placed on the medical specialist to perform the required exclusive diagnosis via detailed medical interviews and examinations of said person and his/her family. Actually, although symptoms such as personality changes, difficulty with the pronunciation of words, memory loss, forgetting the location of items, and forgetting names are seen in early stage Alzheimer's disease, accurately distinguishing the pathological “memory impairment” of early stage Alzheimer's disease from memory impairment due to aging (age-associated memory impairment) is extremely difficult. This also complicates the early detection of Alzheimer's disease, and thus is a major problem.
Moreover, during the early stages, it is thought that a physiological diagnostic marker capable of detecting Alzheimer's disease simply and reliably would be most effective for the objective of screening a large number of people. If early diagnosis or preclinical diagnosis becomes possible by the confirmation a diagnostic marker for Alzheimer's disease, it will allow for the planning of a treatment therapy or the administration of medication based on the confirmed diagnosis thereof, as well as open up new avenues in the prevention of Alzheimer's disease. At the same time, this type of early diagnosis also allows for the high costs required for the care and medical treatment of Alzheimer's patients to be prevented. Thus, the development and invention of a diagnostic marker capable of simply and easily detecting Alzheimer's disease has been strongly desired.
The diagnostic marker, in addition to reflecting the clinical state of Alzheimer's disease, should be both highly sensitive and highly specific to the detection of Alzheimer's disease. Various diagnostic products have so far been proposed from a large number of foreign and domestic groups as diagnostic markers for Alzheimer's disease. For example, the measurements of amyloid β-protein, glycosylated acetylcholine esterase, interleukin-6, substance P, cystatin C, serum apolipoprotein, serum homocysteine, APP isoform, interleukin 6, α1-antichymotrypsin (ACT), oxygenase-1, 24S-hydroxycholesterol, acetylcholine, somatostatin, vasopressin, wheat germ agglutinin (WGA) binding protein, acetylcholine transferase activity, acetylcholine esterase activity, and the like, have been proposed as diagnostic markers for Alzheimer's disease.
Non-patent document 1 discloses the quantitative variations in WGA binding proteins of Alzheimer's disease. Moreover, in non-patent document 2, the glycosylation of transferase and Alzheimer's disease are reviewed.
However, the relationship between the majority of these well-reported diagnostic markers and physiological changes is unclear, and the diagnostic values thereof are not necessarily defined. At present, as diagnostic markers that have been acknowledged as demonstrating clinical efficacy, only two are known, cerebrospinal fluid tau protein and amyloid β42.
Tau protein is the causative agent of a physiological change in which neurofibrillary tangles occur in the brains of Alzheimer's patients. In Alzheimer's disease, there is an increase in phosphorylated tau protein (or overall tau protein) in the cerebrospinal fluid, and thus measuring this tau protein is helpful in the diagnosis of Alzheimer's disease.
The amyloid β-protein employed as the diagnostic marker is an amyloid beta-peptide consisting of 42 amino acids, and the causative agent of a physiological change in which senile plague occurs in the brains of Alzheimer's patients. Since senile plague is manifested by the aggregation of amyloid β-protein in the brains of Alzheimer's patients, the cerebrospinal fluid amyloid β-protein is conversely reduced, and thus measuring this is helpful in the diagnosis of Alzheimer's disease.    Non-Patent Document 1: Lisa R. Fodero, Javier Saez-Valero, Maria-Sagrario Barquero, Alberto Marcos, Catriona A. McLean and David H. Small; “Wheat germ agglutinin-binding glycoproteins are decreased in Alzheimer's disease cerebrospinal fluid”, Journal of Neurochemistry, 2001, 79, 1022-1026; and    Non-Patent Document 2: Susan J. van Rensburg, Peter Berman, Felix Potocnik, Pam MacGregor, Dinie Hon and Nico de Villiers; “5- and 6-glycosylation of transferrin in patients with Alzheimer's disease”, Metabolic Brain Disease, 2004, Vol. 19, 89-96.